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Revivicor Produced Organs Set Records with Pig-to-Primate Transplants

Tuesday, August 25, 2015  
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As reported online in the MIT Technology Review, U.S. researchers have been shattering records in xenotransplantation, or between-species organ transplants, with the financial aid of a biotechnology executive whose daughter may need a lung transplant.

The researchers say they have kept a pig heart alive in a baboon for 945 days and also reported the longest-ever kidney swap between these species, lasting 136 days. The experiments used organs from pigs “humanized” with the addition of as many as five human genes, a strategy designed to stop organ rejection.

The GM pigs are being produced in Blacksburg, Virginia, by Revivicor, a division of the biotechnology company United Therapeutics. That company’s founder and co-CEO, Martine Rothblatt, is a noted futurist who four years ago began spending millions to supply researchers with pig organs and has quickly become the largest commercial backer of xenotransplantation research.

Rothblatt says her goal is to create “an unlimited supply of transplantable organs” and to carry out the first successful pig-to-human lung transplant within a few years. One of her daughters has a usually fatal lung condition called pulmonary arterial hypertension. In addition to GM pigs, her company is carrying out research on tissue-engineered lungs and cryopreservation of organs. “We’re turning xenotransplantation from what looked like a kind of Apollo-level problem into just an engineering task,” she says.

Some researchers agree with Rothblatt that the latest results mean pig-to-human transplants are plausible. “I think it’s possible; it should be considered,” says Leo Bühler, a Swiss transplant surgeon in Geneva. He said he would transplant a genetically engineered pig’s organ into a patient today, were the patient’s situation desperate enough.

And there are desperate cases. In fact, thousands of people die each year while waiting on transplant lists. Donated human organs are scarce, and many that become available don’t end up helping anyone. That is because a heart or kidney lasts only a matter of hours packed in ice, so organs can’t reach any but the closest patients.

“We want to make organs come off the assembly line, a dozen per day,” says Rothblatt. In 2011 her company paid about $8 million to take over Revivicor, and she has outlined plans for a facility able to breed 1,000 pigs a year, complete with a surgical theater and a helipad so organs can be whisked where they are needed.

Researchers continue to work with pigs because they’re in ready supply, and the organs of young pigs are about the right size. In order to beat the rejection problem, researchers began trying to genetically modify the animals. One major step came in 2003 when David Ayares, a cofounder of Revivicor, created pigs whose organs lacked a sugar molecule that normally lines their blood vessels. That molecule was the major culprit behind what’s called hyperacute rejection, which had almost instantaneously destroyed transplanted pig organs.

Removing the sugar molecule helped. But it wasn’t enough. Tests in monkeys showed that other forms of organ rejection still damaged the pig tissue, albeit more slowly. To combat these effects, Ayares’s team has made pigs with more and more human genes. For instance, one gene that’s been added produces the human version of thrombomodulin, a molecule that prevents clotting in blood vessels. Although pigs have their own version of thrombomodulin, it’s the wrong shape and doesn’t work correctly with human blood.

“We are adding the human genes to the pig so you have the organ repressing the immune response, rather than have to give a whopping dose of immune suppressants,” says Ayares. By next year, some of the pigs will have as many as eight added human genes. These genetic changes make their organs more compatible with a human body, but the animals still look and act like normal pigs.

In the United States, leading transplant surgeons have been meeting with Revivicor every few months to plan what genes they’d like to see added next. Since last year, some of the genetic engineering has been carried out in collaboration with Synthetic Genomics, a California company started by DNA sequencing entrepreneur J. Craig Venter. Rothblatt invested $50 million in Venter’s company in 2014, and it has begun designing and building genetic add-ons and inserting them into pig cells. It is left to Revivicor to produce piglets from these engineered cells, using cloning.

Muhammad Mohiuddin, a transplant surgeon and researcher at the National Heart, Lung, and Blood Institute, in Bethesda, Maryland, says he’ll soon begin trying to replace baboon hearts entirely. The organs he used in previous xenotransplants had three genetic alterations, but the next ones will have seven. “If they survive, then we can consider clinical trials,” he says. The first human recipients would be expected to be special cases, like someone who needs an organ as a “bridge” until a human donor becomes available.

Transplant surgeons say one of the largest obstacles they face is the immense cost of carrying out xenotransplant experiments. A single transplant surgery costs $100,000 and involves eight people. Then there’s the cost of keeping the primates, the red tape of animal regulations, and limited government grants. That’s where Rothblatt’s personal interest and her fortune have made a difference, they say. “She is the one that has rejuvenated the field,” says Mohiuddin. “She has the money and a personal attachment. She wants to get it done fast.”

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